DESCRIPTION: Periodontitis is one of the most common inflammatory diseases that afflict humans. The disease is the major cause of tooth loss in adults, affects >50% of the U.S. population, and is treated mainly by local debridement or surgery of the affected teeth. Although the disease is initiated by specific oral pathogens that colonize and invade the oral tissues, the host inflammatory response is a major factor in disease progression. Cytokines such as tumor necrosis factor-alpha (TNF) are found in high levels at periodontal lesions. Soluble protein delivery of antagonists to TNF (TNF receptor: Fc fusion protein) inhibits alveolar bone resorption. Nevertheless, the clinical use of recombinant p75 TNFR: Fc fusion protein raises several concerns, such as reoccurrence of disease activity after cessation of therapy (in the case of rheumatoid arthritis), injection site reactions, and the potential impairment of host immune function. We propose the use of adeno-associated virus (AAV) as an innovative approach to deliver TNFR: Fc to periodontal lesions. As a vector, AAV is a nonpathogenic human virus, and possesses the highly attractive feature of its minimal immunogenicity that allows for long-term transduction. AAV-TNFR: Fc generates the expression of the TNFR: Fc fusion protein, which functions as a TNF antagonist. This proof-of-principle study is designed to determine whether gene delivery of TNFR: Fc in an AAV vector can prevent periodontal disease progression in an experimental animal model of alveolar bone loss. The Specific Aims of this study are to: 1) Determine serum levels and duration of TNFR: Fc protein expression following systemic (intramuscular) and local (interdental gingival tissue) administration of pseudotyped AAV-TNFR: Fc vectors to rats afflicted with LPS-induced periodontitis; and 2) Evaluate the effect of pseudotyped AAV-TNFR: Fc vectors on periodontal bone loss and expression of downstream proinflammatory cytokines in rats with LPS-induced periodontitis. These studies will determine the feasibility of this novel TNFR: Fc delivery strategy to modulate the host response for periodontal disease. The use of AAV-TNF: Fc has significant potential as a therapeutic regimen to treat aggressive periodontitis that is governed by an exuberant inflammatory response.